MRI contrast agents based upon dendrimers obviate the deficiencies of serum albumin or linear polymer based MRI contrast agents of comparable size. Terminal primary amines of dendrimers modified with chelated Gd(III) are developed in our laboratories. These reagents possess a molar relaxivity 6 times that of Magnevist. Excellent conventional whole body MR imaging and 3D T-O-F MR angiograms have been obtained. Studies continue to define the utility and pharmacokinetics and dynamics of these agents. Results have established that macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents can be tuned for various applications by adjusting fundamental criteria: generation (MW & size), core elements (lipophilicity & charge), PEG conjugation, lysine co-administration (renal clearance), and conjugation to targeting vectors (molecular targeting). PAMAM based agents have imaged murine tumor vasculature accurately at the 200 micron scale. DAB based agents have selective properties wherein reverse contrast images of 0.3 mm metastatic liver tumors were detected. These agents have also been selectively targeted, not only by conjugation to antibodies, but by other vectors, such as avidin to deliver exceptionally high levels of Gd(III) into disseminated intraperitoneal ovarian cancer tumor. Recent results include: (1) assessment of chemotherapy induced renal toxicity whereby the MRI images of damaged kidney correlate with standard blood chemistries; (2) imaging of the lymphatic system with particular attention to involvement of the lymph nodes relating to lymphoma; (3) imaging of breast cancer involvement with drainage to sentinel nodes for lymph node involvement diagnosis; and (4) effects of external beam radiation on the integrity of tumor vasculature. Recently extended studies of renal imaging have demonstrated that differentiation between reperfusion injury and sepsis was possible by MRI and was also predictive of time to death from sepsis. The exquisite advantages of the dendrimer based agents over small molecular weight agents has also been very clearly demonstrated. Draining sentinel nodes were clearly defined by MR imaging along with the involved lymphatic vessels in normal mice, transgenic mice that spontaneously develop breast cancer, and in xenograft tumor bearing mice. The response of tumor vasculature to external beam radiation wherein a biological "window" was opened permitting the measured leakage through tumor vessel fenestrations was demonstrated via MRI imaging. The time course kinetics of the opening and closing of this "window" was also determined. We now proceed forward from passively targeted macromolecular MRI contrast agents to the the creation of actively targeted dendrimer based imaging agents that may also be multi-modality imaging agents. Active targeting is pursued via multi-valence incorporation of various peptide element, RGD for example. Another strategy being pursued is site-specific 1:1 conjugation of the dendrimer elements with antibody fragments. Lastly, recent achievements include the creation of multi-modality imaging agent that possesses both chelated Gd(III) for MRI imaging but also incorporates molecules of an infrared dye. This combination permits the combination of the structural resolution of MRI imaging with the sensitivity optical imaging. Current studies of this agent are proceeding in the evaluation of sentinel node imaging in those models established in collaboration with the Molecular Imaging Program.